Transdermal delivery system

ABSTRACT

An improved Transdermal Delivery System (TDS) comprising a backing layer inert to the components of the matrix, a selfadhesive matrix containing an amine-functional drug and a protective foil or sheet to be removed prior to use, characterized in that  
     the self-adhesive matrix consists of a solid or semi-solid semi-permeable polymer  
     (1) wherein an amine functional drug in its free base form has been incorporated,  
     (2) which is saturated with the amine functional drug and contains said drug as a multitude of microreservoirs within the matrix,  
     (3) which is highly permeable for the free base of the amine functional drug,  
     (4) which is impermeable for the protonated form of the amine functional drug,  
     (5) wherein the maximum diameter of the microreservoirs is less than the thickness of the matrix.  
     is provided. Said TDS provides for enhanced flux of the amine functional drug across the TDS/skin interface.

FIELD OF INVENTION

[0001] The present invention relates to an improved transdermal deliverysystem for amine functional drugs. Moreover, the invention relates to amethod of treatment using the transdermal delivery system.

TECHNICAL BACKGROUND

[0002] To date, various transdermal delivery systems (TDS) for theadministration of amine functional drugs, such as rotigotine and manyothers, have been described. WO 94/07568 discloses a TDS containingrotigotine hydrochloride as active substance in a two-phase matrix,which is essentially formed by a hydrophobic polymer material as thecontinuous phase and a disperse hydrophilic phase contained therein andmainly containing the drug and hydrated silica. The silica is said toenhance the maximum possible loading of the TDS with the hydrophilicsalt. Moreover, the formulation of WO 94/07568 usually containsadditional hydrophobic solvents, permeation promoting substancesdispersing agents and, in particular, an emulsifier which is required toemulsify the aqueous solution of the active component in the lipophilicpolymer phase. A TDS prepared by using such a system has been tested inhealthy subjects and Parkinson's patients. However, no satisfactory drugplasma levels were achieved.

[0003] Various further TDS have been described in WO 99/49852. The TDSused in this patent application comprises a backing layer, inert withrespect to the constituents of the matrix, a self-adhesive matrix layercontaining an effective quantity of rotigotine hydrochloride orrotigotine, which contains a substantial amount of rotigotinehydrochloride (>5% w/w), and a protective film, which is to be removedbefore use. The matrix system is composed of a non-aqueous polymeradhesive system, based on acrylate or silicone, with a solubility ofrotigotine of at least 5% w/w. Said matrix has been described as beingessentially free of inorganic silicate particles. However, even the TDSdescribed in WO 99/49852 leave something to be desired as regards theobtainable flux rates of drug across human skin.

[0004] In the TDS according to WO 94/07568 and many relatedapplications, passive diffusion membranes were used.

[0005] However, as the skin is to be seen as a very efficient barrierfor most drug candidates, such type of membrane controlled systems aremore or less limited in practice to transdermal delivery of activesubstances that reveal a very high skin permeability. Additionally,special requirements on drug release kinetics have to be met likecontact delivery over several days.

[0006] An object of the present invention is to control (i.e. tocanalise/manoeuvre) the transport of a drug substance towards and acrossthe skin from a drug reservoir, thereby enhancing the flux of the drugsubstance across the TDS/skin interface.

[0007] A further object and aspect of the present invention is toprovide a suitable composition and manufacturing methods of polymermatrices in TDS which lead to an enhanced delivery of weakly basicamines to and across the skin by

[0008] (i) preventing back diffusion of the drug portion which isionized in the skin according to its pKa value from the skin tissue intothe TDS,

[0009] (ii) offering continuous delivery of the active compound acrossthe stratum corneum not only via the common more lipophilic route (e.g.intercellular) but also through hydrophilic pores (e.g. eccrine sweatglands).

SUMMARY OF THE INVENTION

[0010] These objects are solved by providing a TDS comprising a backinglayer inert to the components of the matrix, a self-adhesive matrixcontaining an amine functional drug and a protective foil or sheet to beremoved prior to use, characterized in that

[0011] the self-adhesive matrix consists of a solid or semi-solidsemi-permeable polymer

[0012] (1) wherein an amine functional drug in its free base form hasbeen incorporated,

[0013] (2) which is saturated with the amine functional drug andcontains said drug as a multitude of microreservoirs within the matrix,

[0014] (3) which is highly permeable for the free base of the aminefunctional drug,

[0015] (4) which is impermeable for the protonated form of the aminefunctional drug,

[0016] (5) wherein the maximum diameter of the microreservoirs is lessthan the thickness of the matrix.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 shows the effect of the protonation of the drug in thesemi-permeable matrix on the drug absorption.

[0018]FIG. 2 shows the impact of the size distribution of themicroreservoirs in the semi-permeable matrix on the drug absorption.

[0019]FIG. 3 shows the effect of reducing the amount of the protonatedform of the drug in the semi-permeable matrix and reducing the size ofthe microreservoirs on the drug absorption.

[0020]FIG. 4 shows a microscope image of a conventional TDS.

[0021]FIG. 5 shows a microscope image of the TDS according to theinvention.

[0022]FIG. 6 shows the effect of reducing the amount of the protonatedform of the drug in the semi-permeable matrix and reducing the size ofthe microreservoirs on the in vitro skin permeation of the drug.

[0023]FIG. 7 shows a comparison of the in vitro skin permeation of thedrug for the TDS of the, invention and an acrylate-based TDS.

DESCRIPTION OF THE INVENTION

[0024] The present invention provides a TDS for amine functional drugsproviding a high steady state flux rate of the amine functional drugover the TDS/skin interface.

[0025] Surprisingly, it was found that drug release properties of a TDShaving a silicone-type adhesive matrix containing an amine functionaldrug can be significantly enhanced by

[0026] (1) minimizing the amount of the amine functional drug which ispresent in the protonated form (salt form);

[0027] (2) incorporating the amine functional drug in a multitude ofmicroreservoirs within the self-adhesive matrix consisting of a solid orsemi-solid semi-permeable polymer.

[0028] The impact of above described measures on drug releasecharacteristics of rotigotine in vivo is illustrated in FIGS. 1, 2 and3. The relative drug absorption in vivo was highest for the sampleaccording to the invention; increase of the size of the microreservoirsand/or the amount of drug salt residues in the TDS led to slower initialdrug release.

[0029] Based on the above findings, the present invention wasaccomplished.

[0030] When using the TDS, according to the present invention, a hightransfer of the amine functional drug from the silicone matrix into theoutermost skin layer can be achieved. Consequently, plasma values of theamine functional drug are sufficient to allow for a reasonableexpectation that an efficient treatment with these drugs with fewer sideeffects can be provided.

[0031] It should be understood that the term “treatment” in the contextof this application is meant to designate a treatment or an alleviationof the symptoms of the diseases that can be treated with the aminefunctional drugs useful in this invention. The treatment may be of atherapeutic or prophylactic nature.

[0032] In a preferred embodiment the amine functional drug incorporatedin the TDS of the present invention has an octanol/water partitioningcoefficient log P>_(—)2.8 at pH 7.4. In another preferred embodiment theamine functional drug has a pKa of 7.4 to 8.4. In an especiallypreferred embodiment the amine functional drug has an octanol/waterpartitioning coefficient log P>_(—)2.8 at pH 7.4 and a pKa of 7.4 to8.4. The pKa-value can be measured by standard methods. A particularlypreferred method is potentiometric titration of aqueous solutions(without addition of organic cosolvents) at room temperature. Theoctanol/water partitioning coefficients (octan-l-of/water partitioningcoefficients) are determined at pH 7.4, 37° C. and an ionic strength of0.15 in an appropriate buffer solution according to the method describedby E. Miyamoto et al. (E. Miyamoto et al. “Physico-chemical Propertiesof Oxybutynin” Analyst (1994), 119, 1489-1492).

[0033] Particularly preferred amine functional drugs are dopamine D2agonists, which are useful for example in the treatment of Parkinson'sdisease. Especially preferred dopamine D2 receptor agonists areaminotetraline compounds, such as5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol(INN: rotigotine).

[0034] Other examples for particularly preferred amine functional drugsare N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide (INN:fentanyl) which is useful in the treatment of pain and anticholinergicdrugs exerting an antispasmodic effect on smooth muscles and inhibitingthe muscarinic action of acetylcholin on smooth muscles. Examples ofsuch anticholinergic drugs which are useful in the present invention are4-diethylamino-2-butynyl phenylcyclohexyl-glycolate (INN: oxybutynine)and 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (INN: fesoterodine). Oxybutynine and fesoterodine are usefulin the treatment of urinary incontinence.

[0035] It will be understood by a person skilled in the art that theamine functional drugs, such as rotigotine, fentanyl, oxybutynine andfesoterodine, may all exist in various isomeric forms. It has to beunderstood that in this case the amine functional drug may be any singleisomer or a mixture of different isomers. If the amine functional groupcontains asymmetric carbon atoms, any single enantiomer or a mixture ofenantiomers may be used. Rotigotine, fentanyl oxybutynine andfesoterodine all contain one asymmetric carbon atom. Hence, the S- orR-enantiomer or the racemate or any other enantiomer mixture of thesecompounds may be used as the amine functional drug.

[0036] At least a part of the amine functional drug is contained in amultitude of microreservoirs distributed within the selfadhesive matrixof the TDS according to the invention. This does not exclude and willnormally even imply that a certain fraction of the amine functional drugis dissolved in the solid or semi-solid semi-permeable polymer of thematrix at its saturation concentration.

[0037] Within this specification “microreservoirs” are meant to beunderstood as particulate, spatially and functionally separatecompartments consisting of pure drug or a mixture of drug andcrystallization inhibitor, which are dispersed in the self-adhesive(polymer) matrix. Preferably the selfadhesive matrix contains 10³ to 10⁹microreservoirs per cm² of its surface, particularly preferred are 10⁶to 10⁹ microreservoirs per cm².

[0038] The amine functional drug is incorporated in the self-adhesivematrix in its free base form. This does not totally exclude the presenceof some residual salt form of the amine functional drug in the finalTDS. However, the salt form of the amine functional drug should becontained in the self-adhesive matrix of the final TDS in an amount ofpreferably less than 5%, more preferably less than 2%, particularly lessthan 1% (w/w).

[0039] If the amine functional drug is present in the self-adhesivematrix in its protonated (salt) form, it will not be released by theself-adhesive matrix. Thus, the amount of the salt form of the aminefunctional drug can be determined by performing a drug dissolution testaccording to the Paddle over Disk method as described in the UnitedStates Pharmacopeia (United States Pharmacopeia/New Formulary(USP25/NF20), Chapter 724 “Drug Release”, United States PharmacopeialConvention, Inc., Rockville, Md. 20852, U.S.A. (2002)), using thefollowing conditions: dissolution medium: 900 ml phosphate buffer pH4.5; temperature adjusted to 32±0.5° C.; paddle rotation speed: 50 rpm;sampling times: 0.5, 1, 2 and 3 h, respectively. The increase in theeluted drug concentration can be used to calculate the amount ofunprotonated drug in the matrix.

[0040] The amount of the salt form of the amine functional drug may bereduced e.g. by reducing the water content of the mass containing thedrug and organic solvent(s). In a particularly preferred embodiment ofthe invention the water content is reduced during manufacture topreferably less than 0.4% (w/w), more preferably less than 0.1%, of themass.

[0041] A further step, which may be taken for reducing the amount of thesalt form of the amine functional drug, is isolating the free base formof the amine functional drug in solid form prior to the preparation ofthe TDS. If the free base of the amine functional drug is produced insitu during the manufacture of the TDS by neutralizing an acid additionsalt, a certain residue of the ionized drug form will remain in thepolymer matrix (usually >5% (w/w) and up to approximately 10%).Therefore, such in situ preparation of the free base form will generallynot be suitable for practising the present invention.

[0042] The maximum diameter of the microreservoirs is less than thethickness of the matrix, preferably up to 70% of the thickness of thematrix, particularly preferably 5 to 60% of the thickness of the matrix.For an exemplary thickness of the matrix of 50 μm this corresponds to amaximum diameter of the microreservoirs in the range of preferably up to35 μm. The term “maximum diameter” is meant to be understood as thediameter of the microreservoirs in one dimension (x-, y-, orz-dimension), which is the largest. It is clear to the skilled personthat in case of spherical diameters the maximum diameter corresponds tothe microreservoir's diameter. However, in the case of microreservoirs,which are not shaped in the form of spheres—i.e. of different geometricforms—, the x-, y- and z-dimensions may vary greatly.

[0043] As the maximum diameter of the microreservoirs in the directionof the cross-section of the matrix, i.e. between the release surface andthe backing layer, is less than the thickness of the matrix, directcontact between the skin and the basic microreservoirs containing theamine-functional drug is avoided, if not at all prevented. Owing to theslightly acidic pH of the skin, direct contact between the skin and themicroreservoirs in the matrix leads to protonation of theamine-functional drug, thereby deteriorating the semi-permeability ofthe matrix.

[0044] In a particularly preferred embodiment of the invention, the meandiameter of the microreservoirs containing the amine functional drugsdistributed in the matrix is in the range of 1 to 40%, even morepreferably 1 to 20%, of the thickness of the drug-loaded self-adhesivematrix. For an exemplary thickness of the matrix of 50 μm thiscorresponds to a mean diameter of the microreservoirs in the range ofpreferably 0.5 to 20 μm. The term “mean diameter” is defined as the meanvalue of the x,y,z-average diameters of all microreservoirs. The targetparticle size can be adjusted by the solids content and viscosity of thedrug-containing coating mass.

[0045] The maximum and mean diameters of the microreservoirs as well asthe number of microreservoirs per surface area of the self-adhesivematrix can be determined as follows: The release liner is removed fromthe TDS, and the free adhesive surface is examined with a lightmicroscope (Leica microscope type DM/RBE equipped with a camera typeBasler A 113C). The measurement is performed by incidental polarizedlight analysis using a microscope at 200×magnification. A pictureanalysis is performed using the software Nikon Lucia_Di, Version 4.21,resulting in mean and maximum diameters for each sample.

[0046] The TDS of the present invention is of the “matrix” type. In suchmatrix type TDS the drug is dispersed in a polymer layer. The TDS of thematrix type in their simplest version comprise a one-phase (monolayer)matrix. They consist of a backing layer, a self-adhesive matrixcontaining the active agent and a protective foil or sheet, which isremoved before use.

[0047] Versions that are more complicated comprise multi-layer matrixes,wherein the drug may be contained in one or more non-adhesive polymerlayers. The TDS of the present invention is preferably a one-phase (monolayer) matrix system.

[0048] The solid or semi-solid semi-permeable polymer of theself-adhesive matrix has to satisfy the following requirements:

[0049] 1. Sufficient solubility and permeability for the free base formof the amine functional drug.

[0050] 2. Impermeability for the protonated form of the amine functionaldrug.

[0051] In a particular preferred embodiment of the invention theself-adhesive matrix is free of particles that can absorb salts of theamine functional drug on the TDS/skin interface. Examples of particlesthat can absorb salts of the amine functional drug on the TDS/Skininterface include silica. Such particles that can adsorb salts of theamine functional drug may represent diffusion barriers for the free baseform of the drug and may result in the formation of channels inducingsome permeability of the self-adhesive matrix for the protonated form ofthe drug. Such embodiments are therefore disadvantageous for practisingthe invention.

[0052] The self-adhesive matrix of the TDS of the present inventionconsists of a solid or semi-solid semi-permeable polymer. Usually thispolymer will be a pressure sensitive adhesive (PSA) or a mixture of suchadhesives. The pressure sensitive adhesive(s) form a matrix in which theactive ingredient and the other components of the TDS are incorporated.

[0053] The adhesive used in the present invention should preferably bepharmaceutically acceptable in a sense that it is biocompatible,non-sensitising and non-irritating to the skin. Particularlyadvantageous adhesives for use in the present invention should furthermeet the following requirements:

[0054] 1. Retained adhesive and co-adhesive properties in the presenceof moisture or perspiration, under normal temperature variations,

[0055] 2. Good compatibility with the amine functional drug, as well aswith the further excipients used in the formulation.

[0056] Although different types of pressure sensitive adhesive may beused in the present invention, it is preferred to use lipophilicadhesives having both a low drug and low water absorption capacity.Particular preferably, the adhesives have solubility parameters whichare lower than those of the amine functional drugs. Such preferredpressure sensitive adhesives for use in the TDS of the present inventionare silicone type pressure sensitive adhesives. Especially preferredpressure sensitive adhesives for use in the TDS of the invention are ofthe type forming a soluble polycondensed polydimethylsiloxane(PDMS)/resin network, wherein the hydroxy groups are capped with e.g.trimethylsilyl (TMS) groups. Preferred adhesives of this kind are theBIO-PSA silicone pressure sensitive adhesives manufactured by DowCorning, particularly the Q7-4201 and Q7-4301 qualities. However, othersilicone adhesives may also be used.

[0057] In a further and especially preferred aspect, two or moresilicone adhesives are used as the main adhesive components. It can beadvantageous if such a mixture of silicone adhesives comprises a blendof high tack silicone pressure sensitive adhesive comprisingpolysiloxane with a resin and a medium tack silicone type pressuresensitive adhesive comprising polysiloxane with a resin.

[0058] Tack has been defined as the property that enables an adhesive toform a bond with the surface of another material upon brief contactunder light pressure (see e.g. “Pressure Sensitive Tack of AdhesivesUsing an Inverted Probe Machine”, ASTM D2979-71 (1982); H. F. Hammond inD. Satas “Handbook of Pressure Sensitive Adhesive Technology” (1989),2^(nd) ed., Chapter 4, Van Nostrand Reinhold, New York, page 38).

[0059] Medium tack of a silicon pressure sensitive adhesive indicatesthat the immediate bond to the surface of another material is weakercompared to high tack silicon adhesive. The mean resin/polymer ratio isapprox. 60/40 for medium tack adhesives, whereas it is approx. 55/45 forhigh tack adhesives. It is known to the skilled person that both tapeand Theological properties are significantly influenced by theresin/polymer ratio (K. L. Ulman and R. P. Sweet “The Correlation ofTape Properties and Rheology” (1998), Information Brochure, Dow CorningCorp., USA).

[0060] Such a blend comprising a high and a medium tack silicone typepressure sensitive adhesive comprising polysiloxane with a resin isadvantageous in that it provides for the optimum balance between goodadhesion and little cold flux. Excessive cold flux may result in a toosoft patch which easily adheres to the package or to patient's garments.Moreover, such a mixture seems to be particularly useful for obtaininghigher plasma levels. A mixture of the aforementioned Q7-4201 (mediumtack) and Q7-4301 (high tack) proved to be especially useful as a matrixfor the TDS according to the present invention.

[0061] In a further preferred embodiment, the TDS further includes acrystallization inhibitor. Several surfactants or amphiphilic substancesmay be used as crystallization inhibitors. They should bepharmaceutically acceptable and approved for use in medicaments. Aparticularly preferred example of such a crystallization inhibitor issoluble polyvinylpyrrolidone, which is commercially available, e.g.under the trademark Kollidon® (Bayer AG). Other suitable crystallizationinhibitors include copolymers of polyvinylpyrrolidone and vinyl acetate,polyethyleneglycol, polypropyleneglycol, glycerol and fatty acid estersof glycerol or copolymers of ethylene and vinyl acetate.

[0062] The device of the present invention further comprises a backinglayer, which is inert to the components of the matrix. This backinglayer is a film being impermeable to the active compounds. Such a filmmay consist of polyester, polyamide, polyethylene, polypropylene,polyurethane, polyvinyl chloride or a combination of the aforementionedmaterials. These films may or may not be coated with an aluminium filmor with aluminium vapour. The thickness of the backing layer may bebetween 10 and 100 μm, preferably between 15 and 40 μm.

[0063] The TDS of the present invention further comprises a protectivefoil or sheet, which will be removed immediately prior to use, i.e.immediately before the TDS will be brought into contact with the skin.The protective foil or sheet may consist of polyester, polyethylene orpolypropylene which may or may not be coated with aluminium film oraluminium vapour or fluoropolymers. Typically the thickness of such aprotective foil or sheet ranges from between 50 and 150 μm. So as tofacilitate removal of the protective foil or sheet when wishing to applythe TDS, the protective foil or sheet may comprise separate protectivefoils or sheets having overlapping edges, similar to the kind used withthe majority of conventional plasters.

[0064] In a preferred embodiment of the present invention, the TDS has abasal surface area of 5 to 50 cm², particularly of 10 to 30 cm². It goeswithout saying that a device having a surface area of, say, 20 cm² ispharmacologically equivalent to and may be exchanged by two 10 cm²devices or four 5 cm² devices having the same drug content per cm².Thus, the surface areas as indicated herein should be understood torefer to the total surface of all devices simultaneously administered toa patient.

[0065] Providing and applying one or several TDS according to theinvention has the pharmacological advantage over oral therapy that theattending physician can titrate the optimum dose for the individualpatient relatively quickly and accurately, e.g. by simply increasing thenumber or size of devices given to the patient. Thus, the optimumindividual dosage can often be determined after a time period of onlyabout 3 weeks with low side effects.

[0066] A preferred content of the amine functional drug in the TDSaccording to the invention is in the range of 0.1 to 2.0 mg/cm². Stillmore preferred are 0.20 to 1.0 mg/cm². If a 7 day patch is desired,higher drug contents will generally be required.

[0067] The device used in the present invention is preferably a patchhaving a continuous adhesive matrix in at least its center portioncontaining the drug. However, transdermal equivalents to such patchesare likewise comprised by the present invention, e.g. an embodimentwhere the drug is in an inert but non-adhesive matrix in the centerportion of the device and is surrounded by an adhesive portion along theedges.

[0068] The TDS according to the present invention is prepared by amanufacturing process, which comprises preparing a drug loaded adhesive,coating, drying or cooling and lamination to get the bulk product,converting the laminate into patch units via cutting, and packaging.

[0069] The invention and the best mode for carrying it out will beexplained in more detail in the following non-limiting examples.

INVENTION EXAMPLE 1 (Very Low Salt Content, Small Microreservoirs)

[0070] 252.6 g Rotigotine free base are dissolved in 587.8 g ethanol100% w/w and mixed with 222.2 g ethanolic solution containing 25% w/wpolyvinylpyrrolidone (Kollidon F 90), 0.11 % w/w aqueous sodiumbisulfite solution (10 % w/w), 0.25% ascorbyl palmitate and 0.62%DL-α-tocopherol. To the homogenous mixture 1692.8 g BIO-PSA Q7 4301 (73%w/w), 1691.6 g BIO-PSA Q7 4201 (73% w/w) and 416.3 g petrol ether areadded and all components are stirred for at least 1 hour to get ahomogenous dispersion.

[0071] For manufacture of the patch matrix, the dispersion is coatedonto a suitable release liner (for example Scotchpak 1022) and thesolvents are continuously removed in a drying oven at temperatures up to80° C. to get a drug-containing adhesive matrix of 50 g/m² coatingweight. The dried matrix film is laminated with a polyester-type backingfoil which is siliconized on the inner side and aluminium vapor coatedon the opposite side.

[0072] The individual patches are punched out of the complete laminateand are sealed into pouches under a nitrogen flow. The rotigotinecontained in the matrix was quantitatively released after 3 hours in thedrug dissolution test according to the Paddle over Disk method asdescribed in the USP using the conditions as described above. Thisresult indicates that the obtained TDS was completely free of rotigotinehydrochloride.

[0073] The mean size of the microreservoirs in the TDS was approx. 10 μmwith typical sizes in the range of 5 to 35 μm. A microscope image of theobtained TDS is shown in FIG. 5.

COMPARATIVE EXAMPLE 1 (High Salt Content, Small Microreservoirs)

[0074] 2400 g Rotigotine hydrochloride were added to a solution of 272.8g NaOH in 3488 g ethanol (96%). The resulting mixture was stirred forapproximately 10 minutes. Then 379.2 g of sodium phosphate buffersolution (27.6 g Na₂HPO₄×2H₂O) and 53.2 g Na₂HPO₄×2H₂O in 298.5 g water)was added. Insoluble or precipitated solids were separated from themixture by filtration. The filter was rinsed with 964 g ethanol (96%) toobtain a particle-free ethanolic solution of rotigotine essentially inthe form of the free base.

[0075] The rotigotine solution (6150 g) in ethanol (30 % w/w) was mixedwith 407 g ethanol (96%). The resulting solution was mixed with 1738.8 gof an ethanolic solution containing 25 wt. % polyvinylpyrrolidone(Kollidone 90F), 0.11 wt. % aqueous sodium bisulfite solution (10 wt.%), 0.25 wt. % ascorbyl palmitate, and 0.62 wt. % DL-alpha-tocopheroluntil homogeneity. To the mixture 13240 g of an amine resistant hightack silicone adhesive (BIO-PSAO Q7-4301 mfd. by Dow Corning) (73 wt. %solution in heptane), 13420 g of an amine resistant medium tack siliconeadhesive (BIO-PSA® Q7-4201 mfd. by Dow Corning) (72 wt. % solution inheptane), and 3073 g petrol ether were added, and all components werestirred until a homogenous dispersion was obtained.

[0076] The dispersion was coated onto a suitable polyester release liner(SCOTCHPAK® 1022) with a suitable doctor knife and the solvents werecontinuously removed in a drying oven at temperatures up to 80° C. forabout 30 minutes to obtain a drug containing adhesive matrix of 50 g/m²coating weight. The dried matrix film was laminated with apolyester-type backing foil (SCOTCHPAK® 1109). The individual patcheswere punched out of the complete laminate in the desired sizes (e.g. 10cm², 20 cm², 30 cm²) and sealed into pouches under the flow of nitrogen.

[0077] Only approx. 95% of the rotigotine contained in the matrix werereleased after 3 hours in the drug dissolution test according to thePaddle over Disk method as described in the USP using the conditions asdescribed above. Thus, the obtained TDS contained approx. 5% (w/w) ofprotonated rotigotine.

[0078] The mean size of the microreservoirs in the TDS was approx. 15 μmwith typical sizes in the range of 10 to 20 μm.

COMPARATIVE EXAMPLE 2 (High Salt Content, Large Microreservoirs)

[0079] 150 g Rotigotine hydrochloride were added to a solution of 17.05g NaOH in 218 g ethanol (96%). The resulting mixture was stirred forapproximately 10 minutes. Then 23.7 g of sodium phosphate buffersolution (8.35 g Na₂HPO₄×2H₂O and 16.07 g NaH₂PO₄×2H₂O in 90.3 g water)was added. Insoluble or precipitated solids were separated from themixture by filtration. The filter was rinsed with 60.4 g ethanol (96%)to obtain a particle-free ethanolic solution of rotigotine essentiallyin the form of the free base.

[0080] The rotigotine solution (346.4 g) in ethanol (35% w/w) was mixedwith 36.2 g ethanol (96%). The resulting solution was mixed with 109 gof an ethanolic solution containing 25 wt % polyvinylpyrrolidone(KOLLIDON® 90F), 0.077 wt % aqueous sodium bisulfite solution (10 wt %),0.25 wt % ascorbyl palmitate, and 0.63 wt % DL-alpha-tocopherol untilhomogenous. To the mixture, 817.2 g of an amine resistant high tacksilicone adhesive (BIO-PSA® Q7-4301 mfd. by Dow Corning) (74 wt %solution in heptane), 851.8 g of an amine resistant medium tack siliconeadhesive (BIO-PSA Q7-4201 mfd. by Dow Corning) (71 wt % solution inheptane), and 205.8 g petrol ether (heptane) were added, and allcomponents were stirred until a homogenous dispersion was obtained.

[0081] The dispersion was coated onto a suitable polyester release liner(SCOTCHPAK® 1022) with a suitable doctor knife and the solvents werecontinuously removed in a drying oven at temperatures up to 80° C. forabout 30 min to obtain a drug-containing adhesive matrix of 50 g/m²coating weight. The dried matrix film was laminated with apolyester-type backing foil (SCOTCHPAK 1109). The individual patcheswere punched out of the complete laminate in the desired sizes (e.g. 10cm², 20 cm², 30 cm²) and sealed into pouches under the flow of nitrogen.

[0082] Owing to the large microreservoirs in the TDS' matrix, it waspossible to dissolve the rotigotine salts by direct contact with thedissolution medium. Thus, it was not possible to determine the amount ofthe protonated form of rotigotine. This indicates that the maximumdiameter of the microreservoirs was larger than the thickness of thematrix.

[0083] The mean size of the microreservoirs in the TDS was approx. 50 μmwith typical sizes in the range of 20 to 90 μm. A microscope image ofthe obtained TDS is shown in FIG. 4. As rotigotine was released fromrotigotine hydrochloride in a manner similar to Comparative Example 1,one may conclude that the obtained TDS also contained 5% (w/w) ofrotigotine in its protonated form.

COMPARATIVE EXAMPLE 3 (Acrylate-type Formulation)

[0084] A mixture of 50.0 g rotigotine hydrochloride and 28.6 g sodiumtrisilicate in 95 g methyl ethyl ketone was stirred at room temperaturefor 48 hours. Subsequently, 17.9 g oleic alcohol, 128.6 g of anacrylic-type adhesive solution (51.4% w/w in ethyl acetate; trade name:Durotak® 387-2287 from NATIONAL STARCH & CHEMICAL), 33.0 g of EUDRAGIT®E100 (from ROEHM PHARMA) (50% w/w solution in ethyl acetate) and 45.0 gethyl acetate were added, and the mass was homogenised mechanically.

[0085] The dispersion was coated onto a suitably siliconised processliner (Hostaphan® RN 100), and the solvents were evaporated at 50° C.over 30 minutes, thereby obtaining a matrix weight of 60 g/m². The dryfilm was laminated with a suitable polyester foil (Hostaphan® RN 15).Individual patches having a desired size of (e.g. 20 cm²) were punchedout of the resulting laminate and sealed into pouches under the flow ofnitrogen.

EXAMPLE 2

[0086] In vivo Drug Absorption Test

[0087] In order to monitor the absorption of the amine functional drugby the human skin the following experiment was carried out. The test wasperformed with the TDS obtained in Example 1 as well as in ComparativeExamples 1 and 2.

[0088] The plasma concentration time profile at different test times wasdetermined in pharmacokinetic studies involving (A) 14 healthy malepersons (TDS of Comparative Examples 2 and 3) or (B) 30 healthy malepersons (TDS of Example 1 and Comparative Example 1), respectively. Thestudies were conducted following an open single-dose randomised (B)two-way or (A) three-way cross-over design.

[0089] Individual concentrations of rotigotine were determined by meansof liquid chromatography and mass spectroscopy. The lower limit ofquantification (LOQ) was 10 pg/ml.

[0090] The drug absorption was calculated from the plasma concentrationdata according to the Wagner-Nelson method (Malcom Rowland, Thomas N.Tozer (Eds.) “Estimation of Adsorption Kinetics from PlasmaConcentration Data” in Clinical Pharmacokinetics, pp 480-483, Williams &Wilkins, 1995), 100%=absorption rate after 48 hours; patch applicationtime was 24 hours.

[0091] A comparison of the flux across human skin for the different TDStested is shown in FIG. 1, 2 and 3.

[0092] In FIG. 1 the rotigotine absorption for the sample obtained inExample 1 containing no salt (◯) is compared to the sample obtained inComparative Example 1 containing approx. 5% (w/w) of rotigotinehydrochloride (). The comparison in FIG. 1 clearly shows that the drugabsorption after patch application depends on the residual salt contentin the semi-permeable matrix and is significantly improved by reducingthe amount of the protonated form of the amine-functional drug presentin the matrix.

[0093]FIG. 2 shows the impact of the size distribution of themicroreservoirs distributed in the semi-permeable matrix by comparingthe sample obtained in Comparative Example 1 having a meanmicroreservoir size of approx. 15 μm and typical sizes between 10 and 20μm () with the sample obtained in Comparative Example 2 having a meanmicroreservoir size of approx. 50 μm and typical sizes between 20 and 90μm (▴). From this comparison it can be deduced that reducing the size ofthe matrix reservoirs significantly increases the flux across the humanskin.

[0094] A comparison between the TDS of Example 1 (◯) and ComparativeExample 2 (▴) is shown in FIG. 3. This comparison clearly indicates thatthe flux across human skin is significantly enhanced by reducing thesalt content and decreasing the size of the microreservoirs.

EXAMPLE 3

[0095] In vitro Diffusion Experiment with Transdermal Drug DeliverySystems

[0096] The test was performed with a sandwich of consecutively asupportive separator membrane, skin and the TDS. Active substance thathas diffused from the TDS through the skin and/or membrane dissolves inan acceptor liquid that continuously passes directly underneath themembrane; the acceptor liquid was collected in tubes in a fractioncollector; and the fractions were analysed for their content ofrotigotine. The flux of active substance through skin was calculated bycorrecting for the influence of the separator membrane.

[0097] The diffusion cell described in Tanojo et al. (Tanojo et al. “Newdesign of a flow through permeation cell for in vitro permeation studiesacross biological membranes” Journal of Controlled Release (1997), 45,41-47) was used in order to conduct the experiment.

[0098] A flask containing the acceptor liquid and the assembleddiffusion cells were placed in a temperature-controlled water-bath(32.0±0.5° C.). The acceptor liquid was continuously pumped from theflask through PTFE tubing by a peristaltic pump, passed through thediffusion cells where the diffusion takes place and was then transportedvia PTFE tubing to test tubes that were placed in a fraction collector.

[0099] The required number of disks was punched out from the TDS byusing a circular knife. Human epidermis, excised to a thickness of200-300 μm from fresh donor skin (storage <36 hours at 4° C.) with adermatome (to be referred to as skin) was spread out on laboratory filmin petridishes. Using the circular knife the required number of diskswas punched out. A disk of membrane was centred on each cell surface.The skin disks were spread out on the membrane disks on the cellsurfaces with the aid of forceps. A disk of the TDS is applied to eachcell, and the cells were assembled. The experiment was then conducted ina manner similar to the one described in Tanojo et al above.

[0100] Afterwards the tubes containing the collected fraction wereweighed, and the contents of each tube were analysed using HPLC.

[0101] This experiment was carried out for the TDS of Example 1 as wellas Comparative Examples 2 and 3.

[0102]FIG. 6 shows the in vitro skin permeation profile for the TDS ofExample 1 () compared to the TDS of Comparative Example 2 (◯).

[0103]FIG. 7 shows the in vitro skin permeation profile for the TDS ofExample 1 () compared to the acrylate TDS of Comparative Example 3 (◯).

[0104] It is clear from the data obtained that the flux across humanskin may be significantly enhanced by controlling the size of themicroreservoirs in the TDS while at the same time providing asemi-permeable matrix, which is highly permeable for the free base ofthe amine functional drug while being impermeable for its protonatedform.

1. A transdermal delivery system (TDS) comprising a backing layer inertto the components of the matrix, a self-adhesive matrix containing anamine-functional drug and a protective foil or sheet to be removed priorto use, characterized in that the self-adhesive matrix consists of asolid or semisolid semi-permeable polymer (1) wherein an aminefunctional drug in its free base form has been incorporated, (2) whichis saturated with the amine functional drug and contains said drug as amultitude of microreservoirs within the matrix, (3) which is highlypermeable for the free base of the amine functional drug, (4) which isimpermeable for the protonated form of the amine functional drug, (5)wherein the maximum diameter of the microreservoirs is less than thethickness of the matrix.
 2. The TDS according to claim 1, characterizedin that the mean diameter of the microreservoirs is in the range of 0.5to 20 μm.
 3. The TDS according to claim 1, characterized in the aminefunctional drug having an octanol/water partitioning coefficient logp≧2.8 at pH 7.4.
 4. The TDS according to claim 1, characterized in theamine functional drug having a pKa of 7.4 to 8.4.
 5. The TDS accordingto claim 1, characterized in that the amine functional drug is adopamine D2 receptor agonist.
 6. The TDS according to claim 5,characterized in that the dopamine D2 receptor agonist is anaminotetraline compound.
 7. The TDS according to claim 6, characterizedin that the aminotetraline compound is rotigotine.
 8. The TDS accordingto claim 1, characterized in that the amine-functional drug is ananticholinergic drug.
 9. TDS according to claim 8, characterized in thatthe anticholinergic drug is oxybutynine.
 10. The TDS according to claim1, characterized in the self-adhesive matrix being free of particlesthat can absorb salts of the amine functional drug at the TDS/skininterface.
 11. The TDS according to claim 1, characterized in that thepolymer matrix comprises a silicone-type pressure sensitive adhesive.12. The TDS according to claim 1, characterized in that the polymermatrix comprises two or more silicone-type pressure sensitive adhesivesas the main adhesive components.
 13. The TDS according to claim 12,wherein the silicone type pressure sensitive adhesive is a blend of ahigh tack silicone type pressure sensitive adhesive comprisingpolysiloxane with a resin and a medium tack silicone type pressuresensitive adhesive comprising polysiloxane with a resin.
 14. Method fortreatment of a patient suffering from a disease treatable by an aminefunctional drug by applying the TDS according to claim 1 to the skin ofthe patient.